Heroin, cocaine, and alcohol addictions, alone and in various combinations of codependency, often with comorbidity and other major medical complications, especially hepatitis C and AIDS, remain major personal and public health problems confronting our nation and the world. Bidirectional translational research, which will be accomplished by interactions among Projects 1, 2, and 3 herein and this project, will allow the expansion of a fundamental understanding of the dynamic molecular neurobiology of specific addictive diseases in stages prior to andduring treatment of a pharmacological or behavioral type. This project will explore the atypical stress responsivity of the hypothalamic-pituitary-adrenal (HPA) axis seen in untreated addictive diseases, including the contributions of the opioid system in the modulation of that axis and interactions with the dopaminergic and glutamatergic systems. Several hypotheses will be tested: 1.1) that buprenorphine, a partial mu agonist with some kappa opioid receptor activity, will permit normalization of the HPA axis; 1.2) that the regulation of anterior pituitary by arginine vasopressin, a possible target for novel therapeutic intervention, becomes altered during cycles of addiction and normalizes during effective treatment; and 1.3) that restoration of normal HPA axis function will occur slowly in cocaine addicts effectively managed with behavioral treatment; 2) that untreated cocaine dependency, with concurrent alcohol or opioid abuse or dependency, will result in significant alterations in normal stress.responsivity; 3) that alterations of stress responsivity will normalize during effective treatment for depression; and 4) that responses to challenge or provocative tests may be different, and even basal levels of hormone may be different, in persons with a specific functional or possibly functional gene variant, or a variant or haplotype, a) associated with an addiction or b) of a gene whose expression is altered by chronic exposure to cocaine or heroin may be related to basal or test response hormone levels. The role of the endogenous opioid system, and other specific components of the HPA axis will be studied with standard and novel challenge compounds, and combinations thereof, including CRF, arginine vasopressin, synthetic ACTH, metyrapone, opioid antagonists dynorphin A(1-13) in patients with specific addictive diseases and normal volunteers.